Gastro-protecting activity of substituted derivatives of 4-phenyl-4-oxo-2-hydroxy-butanoic acid

- Roussel-Uclaf

Diseases and ailments accompanied by gastric and gastroduodenal lesions treated by administering a compound of the formula (I) ##STR1## in which R represents hydrogen or alkyl containing 1 to 5 carbon atoms and R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen, nitro or trifluoromethyl, or R.sub.1 and R.sub.2 form a methylenedioxy group at adjacent carbon atoms, in their racemic and optically active forms, as well as pharmaceutically acceptable salts thereof, particularly alkali metal, alkaline earth metal, or amine salts of said acid.

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Description

The present invention relates to the treatment of diseases and ailments accompanied by gastric and gastroduodenal lesions by administering certain substituted derivatives of 4-phenyl-4-oxo-2-hydroxy-butanoic acid which exhibit gastric acid secretion inhibiting and cytoprotecting activity, and to pharmaceutical compositions containing those compounds.

More particularly, the present invention relates to inhibiting gastric acid secretion with compounds represented by the formula (I) ##STR2## in which R represents hydrogen or alkyl containing 1 to 5 carbon atoms and R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen, nitro or trifluoromethyl, or R.sub.1 and R.sub.2 form a methylenedioxy group at adjacent carbon atoms, in their racemic and optically active forms, as well as pharmaceutically acceptable salts thereof, particularly alkali metal, alkaline earth metal, or amine salts of said acid.

Some of these compounds are known in the art, as for example 4-(2,5-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoic acid disclosed by Pettit et al., J. Org. Chem., 1970, Vol. 35, No. 5, pp. 1367-1376. The gastro-protecting effect of such compounds has not heretofore been reported.

Preferred compounds of formula (I) are those wherein R is as defined above, R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen, nitro group, or trifluoromethyl, in their racemic or optically active forms, as well as the pharmaceutically acceptable alkali metal, alkaline earth metal, or amine salts of said compounds in which R represents hydrogen.

The term "alkyl containing 1 to 5 carbon atoms", includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl and pentyl.

The term "alkoxy containing 1 to 3 carbon atoms" includes, for example, methoxy, ethoxy, n-propoxy and isopropoxy.

The term "halogen atom" includes, for example, chlorine, bromine and fluorine.

The alkali metal or alkaline earth metal salts of compounds of formula (I) in which R represents a hydrogen atom include, for example, sodium salts, potassium salts, lithium salts and calcium salts.

The amine salts of compounds of formula (I), in which R represents a hydrogen atom, are the usual amine salts. Among the usual amines, there can be mentioned the monoalkylamines, such as, for example, methylamine, ethylamine, propylamine; the dialkylamines, such as, for example, dimethylamine, diethylamine, di-n-propylamine; and, trialkylamines, such as, triethylamine. There can likewise be mentioned piperidine, morpholine, piperazine and pyrrolidine.

More preferred compounds of formula (I) are those wherein R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen or nitro in their racemic and optically active forms, as well as the pharmaceutically acceptable alkali metal, alkaline earth metal, or amine salts of the said formula (I) in which R represents hydrogen.

Most preferred of the just mentioned compounds and salts of formula (I) are trhose wherein R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen.

As illustrative of the above compounds, there is mentioned in particular 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxybutanoic acid and 4-(3,5-dimethoxyphenyl)-4-oxo-2-hydroxybutanoic acid.

The compounds of formula (I) above and their salts can be prepared by a process according to which a compound of formula (II):

OCH--COOR (II)

in which R is as defined before is caused to react with an acetophenone of formula (III): ##STR3## in which R.sub.1 and R.sub.2 have the meaning defined above, to obtain a corresponding product of formula (I) which, if desired, is converted into a salt or ester by the usual methods.

Under the preferred conditions of operation, the process described above is carried out in the following manner:

Condensation of the product of formula (II) and the product of formula (III) is carried out at a temperature between 60.degree. C. and 120.degree. C. using an excess of the product of formula (III). However, when the product of formula (II) in which R represents hydrogen is used, the operation can be carried out with equal advantage at room temperature in the presence of a catalyst such as an alkaline agent (sodium hydroxide, potassium hydroxide, for example).

The operation can likewise be carried out in the presence of a solvent such as an aromatic or aliphatic hydrocarbon (benzene, toluene, heptane, for example).

The products of formula (I) above, in which R represents hydrogen, can likewise be prepared by a process according to which a product of formula (IV): ##STR4## in which R.sub.1 and R.sub.2 have the value indicated above, is condensed with water in an acid medium.

Under preferred conditions of carrying out the latter process, the operation is as follows:

Hydration is carried out at a temperature ranging from 60.degree. C. to the reflux temperature of the reaction medium. The acid utilized can be, for example, hydrochloric acid, sulfuric acid, or phosphoric acid.

The alkali metal, alkaline earth metal, or amine salts of the products of formula (I) can be prepared in the usual manner, by reaction of the said products of formula (I) with the corresponding bases.

The above described compounds according to the invention are very useful in human therapy, particularly for the treatment of hyperchlorhydria, gastric ulcers, gastroduodenal ulcers, gastritis, hiatal hernias, and gastroduodenal diseases accompanied by gastric hyperacidity.

Dosage, which is variable according to the specific product utilized and the disease in question, can range, for example, between 0.05 and 2 g, preferably between 0.2 g and 1.5 g per day in adults via oral administration.

A further object of the present invention is to provide pharmaceutical compositions which contain, as the active ingredient, at least one of the above-mentioned compounds. These compositions are prepared so as to be administrable by the digestive or parenteral route.

They can be solid or liquid and can be embodied in the pharmaceutical forms at present utilized in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, or injectable preparations, all of which can be prepared by the usual methods.

The active principle or principles can be incorporated in excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty materials of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, and preservatives.

The examples presented below are for the purpose of illustrating the invention without, however, limiting it to these specific embodiments.

EXAMPLE 1 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoic acid

22.2 g of glyoxylic acid, 50% by weight in water, are heated under reduced pressure until about 80% of the water present is eliminated; then, after cooling, 54 g of 3,4-dimethoxyacetophenone are introduced into the reaction medium, i.e., a 100% excess over theoretical.

Heating is performed for 150 minutes at 95.degree. C. under reduced pressure, the water present being simultaneously distilled off.

Then, after cooling of the medium to room temperature, there are introduced 60 cm.sup.3 of ether and 100 cm.sup.3 of distilled water containing 8.7 g of pure, dry sodium carbonate.

After decantation, the organic phase is washed with ether, then the united aqueous phases are acidified to pH 1 with 6 N hydrochloric acid. The desired product is then extracted with ethyl acetate. After washing, drying and elimination of the extraction solvent under vacuum, 37 g of the desired product are isolated in the form of an oil, which crystallizes spontaneously on cooling.

After recrystallization in 1,2-dichloroethane, there are obtained 19.7 g of 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxybutanoic acid.

m.p.=107.+-.1.degree. C.

  ______________________________________                                    

     Analysis                                                                  

                    C %  H %                                                   

     ______________________________________                                    

     Calculated       56.69  5.55                                              

     Found            56.5   5.5                                               

     ______________________________________                                    

NMR Spectrum:

The product was analyzed in solution in D.sub.6 acetone with trimethylsilane as the reference material.

The chemical displacements of protons in the groups --CH.sub.2 --CH(OH)-- and --OCH.sub.3 are given below: S=3.35 ppm, d, 2H, J=6 Hz; S=3.8 ppm, 2S, 6H; S=4.66 ppm, t, 1H, J=6 Hz.

Acidimetry (expressed as percentage of theoretical)=98.8%.

By the action of diazomethane on the product obtained above, 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoic acid, there was obtained methyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoate.

m.p.=103.+-.1.degree. C.

  ______________________________________                                    

     Analysis (C.sub.13 H.sub.16 O.sub.6)                                      

                    C %  H %                                                   

     ______________________________________                                    

     Calculated:      58.20  6.01                                              

     Found:           58.1   6.1                                               

     ______________________________________                                    

EXAMPLES 2-12

The products of the following Examples 2-12 were prepared by proceeding in the manner described in Example 1, starting from glyoxylic acid and an acetophenone correspondingly substituted in the phenyl nucleus. The products and their characteristics are set forth in the following Tables 1 and 2.

                                    TABLE 1                                 

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                                        m.p. and                               

                           Empirical                                           

                                  Molecular                                    

                                        recrystallization                      

     Example No.                                                               

            Product        formula                                             

                                  weight                                       

                                        solvent*                               

     __________________________________________________________________________

     2      4-(4-chlorophenyl)-4-oxo-2-                                        

                           C.sub.10 H.sub.9 ClO.sub.4                          

                                  228.6 137.degree. C. (a)                     

            hydroxy-butanoic acid                                              

     3      4-(3,4-dichlorophenyl)-4-oxo-                                      

                           C.sub.10 H.sub.8 Cl.sub.2 O.sub.4                   

                                  263.1 146.degree. C. (b)                     

            2-hydroxy-butanoic acid                                            

     4      4-(2,4-dichlorophenyl)-4-oxo-                                      

                           C.sub.10 H.sub.8 Cl.sub.2 O.sub.4                   

                                  263.1  77.degree. C. (a)                     

            2-hydroxy-butanoic acid                                            

     5      4-(4-bromophenyl)-4-oxo-2-                                         

                           C.sub.10 H.sub.9 BrO.sub.4                          

                                  273.1 149.degree. C. (c)                     

            hydroxy-butanoic acid                                              

     6      4-(4-fluorophenyl)-4-oxo-2-                                        

                           C.sub.10 H.sub.9 FO.sub.4                           

                                  212.2 127.degree. C. (a)                     

            hydroxy-butanoic acid                                              

     7      4-(3-nitrophenyl)-4-oxo-2-                                         

                           C.sub.10 H.sub.9 NO.sub.6                           

                                  239.2 138.degree. C. (b)                     

            hydroxy-butanoic acid                                              

     8      4-(4-nitrophenyl)-4-oxo-2-                                         

                           C.sub.10 H.sub.9 NO.sub.6                           

                                  239.2 108.degree. C. (b)                     

            hydroxy-butanoic acid                                              

     9      4-(2,4-dimethoxyphenyl)-4-oxo-                                     

                           C.sub.12 H.sub.14 O.sub.6                           

                                  254.24                                       

                                        106.degree. C. (a)                     

            2-hydroxybutanoic acid                                             

     10     4-(2,5-dimethoxyphenyl)-4-oxo-                                     

                           C.sub.12 H.sub.14 O.sub.6                           

                                  254.24                                       

                                         89.degree. C. (a)                     

            2-hydroxy-butanoic acid                                            

     11     4-(3,5-dimethoxyphenyl)-4-oxo-                                     

                           C.sub.12 H.sub.14 O.sub.6                           

                                  254.24                                       

                                        119.degree. C. (a)                     

            2-hydroxy-butanoic acid                                            

     12     4-(4-trifluoromethylphenyl)-                                       

                           C.sub. 11 H.sub.9 F.sub.3 O.sub.4                   

                                  262.18                                       

                                        119.degree. C. (a)                     

            4-oxo-2-hydroxy-butanoic acid                                      

     __________________________________________________________________________

      *Recrystallization solvents:                                             

      (a) = 1,2dichloroethane,                                                 

      (b) = ethyl acetate,                                                     

      (c) = methyl ethyl ketone                                                

                                    TABLE 2                                 

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                            Acidimetry                                         

            Elemental Analyses                                                 

                            expressed as                                       

     Example No.                                                               

            Found (calculated)                                                 

                            % of theory                                        

                                   NMR**                                       

     __________________________________________________________________________

     2      C % 52.6 (52.53) H % 4.0 (3.97)                                    

                            98.5%  S = 3.45 ppm, d, 2H, J = 6Hz                

            Cl % 15.6 (15.51)      S = 4.7 ppm, t, 1H, J = 6Hz                 

     3      C % 45.5 (45.65) H % 3.1 (3.07)                                    

                            99.2%                                              

            Cl % 26.8 (26.95)                                                  

     4      C % 45.7 (45.65) H % 3.0 (3.07)                                    

                            100%                                               

            Cl % 26.8 (26.95)                                                  

     5      C % 44.1 (43.98) H % 3.4 (3.32)                                    

                             99%                                               

            Br 29.2 (29.26)                                                    

     6      C % 56.7 (56.61) H % 4.3 (4.28)                                    

                            98.8%                                              

     7      C % 50.2 (50.22) H % 3.8 (3.79)                                    

                            99.6%                                              

            N % 5.9 (5.86)                                                     

     8      C % 50.3 (50.22) H % 3.9 (3.79)                                    

                            98.7%                                              

            N % 5.8 (5.86)                                                     

     9      C % 56.7 (56.69) H % 5.65 (5.55)                                   

                            99.3%                                              

     10     C % 56.5 (56.69) H % 5.4 (5.55)                                    

                            100%                                               

     11     C % 56.0 (56.69) H % 5.5 (5.55)                                    

                            98.9%                                              

     12     C % 50.4 (50.39) H % 3.5 (3.46)                                    

                            99.3%  S = 3.52 ppm, d, 2H, J = 6Hz                

                                   S = 4.7 ppm, t, 1H, J = 6Hz                 

     __________________________________________________________________________

      **NMR Spectrum: The products were analyzed in solution in acetone with   

      trimethylsilane as the reference material. The chemical displacements of 

      protons in the --CH.sub.2 --CH(OH)-- group are given.                    

EXAMPLE 13 4-(2-nitrophenyl)-4-oxo-2-hydroxy-butanoic acid

4-(2-nitrophenyl)-4-oxo-2-butenoic acid is hydrolyzed in solution in 80 volumes of about 2 N hydrochloric acid under reflux for 24 hours.

m.p.=108.degree. C. (crystallization in 1,2-dichloroethane).

  ______________________________________                                    

     Analysis:                                                                 

               C %        H %    N %                                           

     ______________________________________                                    

     Calculated: 50.22        3.79   5.86                                      

     Found:      50.1         3.8    5.7                                       

     ______________________________________                                    

Acidimetry (expressed as percentage of theoretical)=98.8%

EXAMPLE 14 4-(3,4-methylenedioxyphenyl)-4-oxo-2-hydroxy-butanoic acid

29.6 g (0.2 M) of glyoxylic acid, 50% in water, are heated under reduced pressure until about 80% of the water present has been eliminated; then, after cooling, 65.5 g (0.4 M) of 3', 4'-methylenedioxyacetophenone are introduced into the reaction medium. Heating is performed for 3 hours at 95.degree. C. under reduced pressure, the residual water present being simultaneously distilled off. After the medium has been cooled, there are introduced 200 cm.sup.3 of chloroform and 400 cm.sup.3 of water containing 12 g of sodium carbonate.

After decantation, the aqueous phase is washed with chloroform, then acidified to pH 1 with 6 N hydrochloric acid. After filtering and drying, there are obtained 20.6 g of the expected product.

m.p.=159.degree. C.

  ______________________________________                                    

     Analysis (C.sub.11 H.sub.10 O.sub.6) = 238.2                              

                    C %  H %                                                   

     ______________________________________                                    

     Calculated:      55.47  4.23                                              

     Found:           55.6   4.3                                               

     ______________________________________                                    

EXAMPLE 15 Pharmaceutical Forms

(a) Tablets

Tablets were prepared corresponding to the following formulation:

  ______________________________________                                    

     4-(3,4-dimethoxyphenyl-4-oxo-2-hydroxy-butanoic acid                      

                                  100 mg                                       

     Excipient q.s. for a finished tablet to                                   

                                  300 mg                                       

     (details of excipient: lactose, wheat starch, treated                     

     starch, rice starch, magnesium stearate, talc).                           

     ______________________________________                                    

(b) Capsules

Capsules were prepared corresponding to the following formulation:

  ______________________________________                                    

     4-(4-fluorophenyl)-4-oxo-2-hydroxy-butanoic acid                          

                                100 mg                                         

     Excipient q.s. for a finished capsule to                                  

                                300 mg                                         

     (details for excipient: talc, magnesium sterate,                          

     aerosil)                                                                  

     ______________________________________                                    

PHARMACOLOGICAL STUDY (1) Determination of anti-ulcer activity

The method used is described by Shay et al. in Gastroenterology, 5, 43, (1945).

The Shay method consists of inducing ulcers in rats in the stomach region by pyloric ligation.

The animals are anesthetized with ether. A longitudinal incision is made, 1 cm below the sternum; the glandular part of the stomach and the duodenum are exposed, and a ligature is placed several mm below the pylorus. The muscular sheet is left as it is and the skin is sutured with 2 clips.

The animals immediately receive the dispersive or the substance to be studied, via the mouth, in a volume of 0.5 ml/100 g and are kept without food or drink until sacrificed, 16 hours after the treatment, by carotid bleeding.

Before removal of the stomach, a ligature is placed above the cardia.

The gastric liquid is collected for measurement of pH.

The stomach is then opened along the major curvature, rinsed with physiological serum, and spread out on millimeter graph paper to be examined under a binocular magnifier.

The severity of the lesions, graded 0 to 4, is macroscopically evaluated for each stomach.

For each group of rats, the mean intensity of the ulcerations is determined, and the protection is calculated as the ratio of the mean index for the treated group to the mean index for the control group.

The pH values of the gastric liquid are likewise determined for the treated and control animals.

The results obtained are reported in the following Table 3.

                TABLE 3                                                     

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                             Ulcerations                                       

                 pH of gastric liquid                                          

                             % of protection                                   

     Product of                                                                

              Dose     treated  control                                        

                                       with respect to                         

     Example  (mg/kg)  animals  animals                                        

                                       controls                                

     ______________________________________                                    

     1        20       2.3      3.4    72%                                     

              4        3.0      2.8    72%                                     

              0.8      3.4      2.8    27%                                     

     2        20       3.0      3.4    72%                                     

              4        3.5      2.8    25%                                     

     3        100      4.2      2.3    91%                                     

              20       3.2      2.8    36%                                     

     4        100      4.4      2.3    91%                                     

              20       2.9      2.8     9%                                     

     5        100      3.4      2.3    95%                                     

              20       3.1      3.4    40%                                     

     8        100      3.0      2.3    49%                                     

     11       100      3.0      2.0    88%                                     

              20       2.0      1.8    60%                                     

              4        2.0      2.6    50%                                     

              1        1.9      2.2    53%                                     

     ______________________________________                                    

(2) Determination of Acute Toxicity

The lethal dose LD.sub.50 of the derivatives of certain examples were evaluated after administration by the oral route in mice.

The following results obtained are set forth in the following Table 4.

                TABLE 4                                                     

     ______________________________________                                    

     Product of                                                                

     Example       LD.sub.50 (mg/kg)                                           

     ______________________________________                                    

     1             >1000                                                       

     2             >1000                                                       

     3             >1000                                                       

     4             >1000                                                       

     5             >1000                                                       

     8             >1000                                                       

     11            >1000                                                       

     13            >1000                                                       

     ______________________________________                                    

The above examples are illustrative of the invention, but are not to be deemed limitative. It is obvious to one skilled in the art that equivalent techniques and modifications may be employed without departing from the spirit of the invention and the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising as the active ingredient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound selected from the group consisting of a substituted derivative of 4-phenyl-4-oxo-2-hydroxy-butanoic acid of the formula (I) ##STR5## in which R represents hydrogen or alkyl group containing 1 to 5 carbon atoms and R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen, nitro or trifluoromethyl, or R.sub.1 and R.sub.2 form a methylenedioxy group at adjacent carbon atoms, in their racemic or optically active forms, and pharmaceutically acceptable salts of said acid and a pharmaceutically acceptable carrier.

2. The composition according to claim 1, wherein R is as defined in claim 1 and R.sub.1 and R.sub.2 both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen, nitro or a trifluoromethyl group.

3. The composition according to claim 2, wherein R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen or nitro.

4. The composition according to claim 2, wherein R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms, or both represent halogen, or R.sub.1 represents hydrogen and R.sub.2 represents halogen.

5. The composition according to claim 2, wherein R.sub.1 and R.sub.2, identical or different, both represent alkoxy containing 1 to 3 carbon atoms.

6. The composition according to claim 1, 2, 3, 4 or 5, wherein said pharmaceutically acceptable salts are selected from the group consisting of alkali metal, alkaline earth metal and amine salts.

7. The composition according to claim 1, wherein the compound is 4-(3,4-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoic acid.

8. The composition according to claim 1, wherein the compound is 4-(3,5-dimethoxyphenyl)-4-oxo-2-hydroxy-butanoic acid.

9. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 1.

10. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 2.

11. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion and cytoprotecting inhibiting effective amount of a compound as defined in claim 3.

12. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion and cytoprotecting inhibiting effective amount of a compound as defined in claim 4.

13. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 5.

14. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 6.

15. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 7.

16. A method of treating a patient suffering from a gastric or gastroduodenal disease accompanied by gastric hyperacidity comprising administering to said patient a gastric acid secretion inhibiting and cytoprotecting effective amount of a compound as defined in claim 8.

17. The method according to claim 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient treated is suffering from hyperchlorhydria.

18. The method according to claim 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient treated is suffering from gastric ulcer or gastroduodenal ulcer.

19. The method according to claim 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient is suffering from gastritis.

20. The method according to claim 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient treated is suffering from hiatal hernia.

Referenced Cited
U.S. Patent Documents
2532579 December 1950 Thomas
2562208 July 1951 Papa et al.
3753997 August 1973 Ash et al.
3763148 October 1973 Ash et al.
3846470 November 1974 Raube et al.
3910959 October 1975 Vallet
3940404 February 24, 1976 Ash et al.
3940487 February 24, 1976 La Croix et al.
3953463 April 27, 1976 Ash et al.
4017517 April 12, 1977 Murata et al.
Foreign Patent Documents
1282644 September 1962 DEX
2047806 April 1972 DEX
2103749 August 1972 DEX
2501834 July 1975 DEX
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Other references
  • Journal of American Pharmaceutical Association, vol. 37, No. 11, Nov. 1948, pp. 439-449. Chemical Abstracts, vol. 88, No. 5, Jan. 30, 1978 Abstract 37442p. Journal of the American Chemical Society, vol. 71, No. 4, Apr. 1949, F. K. Kirchner et al., pp. 1210-1213. Journal of the American Chemical Society, vol. 70, No. 10, Oct. 1948, D. Papa et al., pp. 3356-3360. European Journal of Medical Chemistry Chimica Therapeutica, vol. 12, Jan.-Feb. 1977, pp. 17-20. European Journal of Medical Chemistry Chimica Therapeutica, vol. 13, No. 3, May-Jun. 1978, H. Orzalesi et al., pp. 259-264. Beilstein, vol. 19, p. 312. Journal of Pharmaceutical Sciences, vol. 66, No. 4, Apr. 1977, pp. 466-476, Child, Ralph G., et al., "Fenbufen, a New Anti-Inflammatory Analgesic: Synthesis and Structure--Activity Relationships of Analogs". Journal of Medicinal Chemistry, vol. 15, No. 9, Sep. 1972, pp. 918-922, Markovac, A., et al.,--"Antimalarials 3, 2,6-Bis(aryl)-4-pyridinemethanols with Trifluoromethyl Substituents". Journal of Organic Chemistry, vol. 35, No. 5, May 1970, pp. 1367-1376, Pettit, George R., et al., "Bufadienolides 1., Introduction and Base-Catalyzed Condensation of Methyl Ketonds with Glyoxylic Acid". J.A.C.S., vol. 46, No. 10, Oct. 1924, pp. 2319-2326 Rice, Grace Potter, "The Isomeric Esters of Para-Ethoxy-Benzoylacrylic Acid".
Patent History
Patent number: 4402978
Type: Grant
Filed: Apr 23, 1981
Date of Patent: Sep 6, 1983
Assignee: Roussel-Uclaf (Romainville)
Inventors: Yani Christidis (Paris), Robert Fournex (Paris), Colette Tournemine (Livry-Gargan)
Primary Examiner: Frederick E. Waddell
Law Firm: Stevens, Davis, Miller & Mosher
Application Number: 6/256,911
Classifications
Current U.S. Class: 424/317; 424/308; 424/309; 424/282
International Classification: A61K 3119; A61K 31235; A61K 3124;